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Protein

Mothers against decapentaplegic homolog 3

Gene

SMAD3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.11 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei40Required for trimerization1
Sitei41Required for interaction with DNA and JUN and for functional cooperation with JUN1
Metal bindingi64Zinc1
Metal bindingi109Zinc1
Metal bindingi121Zinc1
Metal bindingi126Zinc1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDNA-binding
Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-1181150 Signaling by NODAL
R-HSA-1502540 Signaling by Activin
R-HSA-2173788 Downregulation of TGF-beta receptor signaling
R-HSA-2173789 TGF-beta receptor signaling activates SMADs
R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-3304356 SMAD2/3 Phosphorylation Motif Mutants in Cancer
R-HSA-3311021 SMAD4 MH2 Domain Mutants in Cancer
R-HSA-3315487 SMAD2/3 MH2 Domain Mutants in Cancer
R-HSA-3656532 TGFBR1 KD Mutants in Cancer
R-HSA-5689880 Ub-specific processing proteases
R-HSA-8941855 RUNX3 regulates CDKN1A transcription
R-HSA-8952158 RUNX3 regulates BCL2L11 (BIM) transcription
R-HSA-9008059 Interleukin-37 signaling
R-HSA-9013695 NOTCH4 Intracellular Domain Regulates Transcription
SignaLinkiP84022
SIGNORiP84022

Protein family/group databases

MoonDBiP84022 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
Mothers against decapentaplegic homolog 3
Short name:
MAD homolog 3
Short name:
Mad3
Short name:
Mothers against DPP homolog 3
Short name:
hMAD-3
Alternative name(s):
JV15-2
SMAD family member 3
Short name:
SMAD 3
Short name:
Smad3
Short name:
hSMAD3
Gene namesi
Name:SMAD3
Synonyms:MADH3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

EuPathDBiHostDB:ENSG00000166949.15
HGNCiHGNC:6769 SMAD3
MIMi603109 gene
neXtProtiNX_P84022

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Colorectal cancer (CRC)1 Publication
The disease may be caused by mutations affecting the gene represented in this entry.
Disease descriptionA complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
See also OMIM:114500
Loeys-Dietz syndrome 3 (LDS3)2 Publications
The disease is caused by mutations affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.1 Publication
Disease descriptionAn aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation.
See also OMIM:613795
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067051112A → V in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906854EnsemblClinVar.1
Natural variantiVAR_067047239E → K in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906853EnsemblClinVar.1
Natural variantiVAR_065578261T → I in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906851EnsemblClinVar.1
Natural variantiVAR_067048279R → K in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906852EnsemblClinVar.1
Natural variantiVAR_065579287R → W in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906850EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi8T → V: Reduced phosphorylation, increased transcriptional and antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-179 and A-213. 1 Publication1
Mutagenesisi33K → R: Slightly decreased monoubiquitination. 1 Publication1
Mutagenesisi40K → A: Little effect on interaction with DNA or JUN. Abolishes interaction with DNA and JUN; when associated with A-41; A-43 and A-44. 1 Publication1
Mutagenesisi41K → A: Greatly reduced interaction with DNA and JUN. Abolishes interaction with DNA and JUN; when associated with A-40; A-44 and A-43. 1 Publication1
Mutagenesisi43K → A: Little effect on interaction with DNA or JUN. Abolishes interaction with DNA and JUN; when associated with A-40; A-41 and A-44. 1 Publication1
Mutagenesisi44K → A: Little effect on interaction with DNA or JUN. Abolishes interaction with JUN; when associated with A-40; A-41 and A-43. 1 Publication1
Mutagenesisi53K → R: Slightly decreased monoubiquitination. 1 Publication1
Mutagenesisi74R → D: Reduced interaction with JUN. Loss of transcriptional activity and cooperation with JUN. 1 Publication1
Mutagenesisi81K → R: Decreased monoubiquitination. 1 Publication1
Mutagenesisi179T → V: Reduced phosphorylation, increased transcriptional and increased antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-8 and A-213. 3 Publications1
Mutagenesisi204S → A: Increased transcriptional activity. Further increased transcriptional activity; when associated with S-208. 3 Publications1
Mutagenesisi208S → A: Increased transcriptional activity. Further increased transcriptional activity; when associated with S-208. 3 Publications1
Mutagenesisi213S → A: Reduced phosphorylation. Increased transcriptional and antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-8 and V-179. 1 Publication1
Mutagenesisi333K → R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-341; R-378 and R-409. 1 Publication1
Mutagenesisi341K → R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-378 and R-409. 1 Publication1
Mutagenesisi378K → Q: Increased transcriptional activity. No further increase in transcriptional activity with EP300. 1 Publication1
Mutagenesisi378K → R: Greatly reduced acetylation and 85% reduction in transcriptional activity. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-341 and R-409. 1 Publication1
Mutagenesisi409K → R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-341 and R-378. 1 Publication1
Mutagenesisi418S → A: Increased constitutive activity. 1 Publication1
Mutagenesisi418S → D: Decreased activity. 1 Publication1
Mutagenesisi422 – 425SSVS → AAVA: Does not abolish protein nuclear export. Abolishes almost completely acetylation. 3 Publications4
Mutagenesisi422 – 425SSVS → EEVE: Forms heterotrimers. 3 Publications4
Mutagenesisi422 – 425SSVS → RRVR: Diminishes cargo protein export. 3 Publications4

Keywords - Diseasei

Aortic aneurysm, Disease mutation

Organism-specific databases

DisGeNETi4088
GeneReviewsiSMAD3
MalaCardsiSMAD3
MIMi114500 phenotype
613795 phenotype
OpenTargetsiENSG00000166949
Orphaneti284984 Aneurysm-osteoarthritis syndrome
91387 Familial thoracic aortic aneurysm and aortic dissection
PharmGKBiPA30526

Chemistry databases

ChEMBLiCHEMBL1293258

Polymorphism and mutation databases

BioMutaiSMAD3
DMDMi51338669

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000908562 – 425Mothers against decapentaplegic homolog 3Add BLAST424

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1
Modified residuei8Phosphothreonine; by CDK2 and CDK41 Publication1
Cross-linki33Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki81Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei179Phosphothreonine; by CDK2, CDK4 and MAPK3 Publications1
Modified residuei204Phosphoserine; by GSK3 and MAPKPROSITE-ProRule annotation3 Publications1
Modified residuei208Phosphoserine; by MAPKPROSITE-ProRule annotation3 Publications1
Modified residuei213Phosphoserine; by CDK2 and CDK4PROSITE-ProRule annotation1 Publication1
Modified residuei378N6-acetyllysine1 Publication1
Modified residuei416PhosphoserineCombined sources1
Modified residuei418Phosphoserine; by CK1PROSITE-ProRule annotation1 Publication1
Modified residuei422Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity1
Modified residuei423Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity1
Modified residuei425Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity1

Post-translational modificationi

Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G1/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.10 Publications
Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.1 Publication
Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.1 Publication
Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (By similarity). Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385).By similarity2 Publications

Keywords - PTMi

Acetylation, ADP-ribosylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP84022
MaxQBiP84022
PaxDbiP84022
PeptideAtlasiP84022
PRIDEiP84022
ProteomicsDBi57743
57744 [P84022-2]
57745 [P84022-3]

PTM databases

iPTMnetiP84022
PhosphoSitePlusiP84022

Expressioni

Gene expression databases

BgeeiENSG00000166949 Expressed in 229 organ(s), highest expression level in amniotic fluid
CleanExiHS_SMAD3
ExpressionAtlasiP84022 baseline and differential
GenevisibleiP84022 HS

Organism-specific databases

HPAiCAB008094
CAB069409
HPA046386
HPA067203

Interactioni

Subunit structurei

Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with TGFBR1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3. Interacts with AIP1, TGFB1I1, TTRAP, FOXL2, PML, PRDM16, HGS, WWP1 and SNW1. Interacts (via MH2 domain) with CITED2 (via C-terminus). Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts (via the MH2 domain) with ZFYVE9. Interacts with HDAC1, VDR, TGIF and TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and TGFB1I1. Interacts with DACH1; the interaction inhibits the TGF-beta signaling. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex with SMAD3, RAN and XPO4. Interacts in the complex directly with XPO4. Interacts (via the MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with WWTR1 (via its coiled-coil domain). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with SKI; the interaction represses SMAD3 transcriptional activity. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta. Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling. Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts with PMEPA1. Interacts with ZC3H3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with ZFHX3. Interacts weakly with ZNF8 (PubMed:12370310). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (By similarity). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (PubMed:24613385).By similarity43 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi110263, 348 interactors
ComplexPortaliCPX-1 SMAD2-SMAD3-SMAD4 complex
CPX-12 SMAD3 homotrimer
CPX-3252 SMAD3-SMAD4 complex
CORUMiP84022
DIPiDIP-29720N
IntActiP84022, 188 interactors
MINTiP84022
STRINGi9606.ENSP00000332973

Chemistry databases

BindingDBiP84022

Structurei

Secondary structure

1425
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP84022
SMRiP84022
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP84022

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 136MH1PROSITE-ProRule annotationAdd BLAST127
Domaini232 – 425MH2PROSITE-ProRule annotationAdd BLAST194

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni137 – 231LinkerAdd BLAST95
Regioni271 – 324Sufficient for interaction with XPO41 PublicationAdd BLAST54

Domaini

The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding.
The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.
The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated

Phylogenomic databases

eggNOGiKOG3701 Eukaryota
ENOG410XQKU LUCA
GeneTreeiENSGT00760000119091
HOGENOMiHOG000286018
HOVERGENiHBG053353
InParanoidiP84022
KOiK04500
OMAiSDHQMTH
OrthoDBiEOG091G082C
PhylomeDBiP84022
TreeFamiTF314923

Family and domain databases

Gene3Di2.60.200.10, 1 hit
3.90.520.10, 1 hit
InterProiView protein in InterPro
IPR013790 Dwarfin
IPR003619 MAD_homology1_Dwarfin-type
IPR013019 MAD_homology_MH1
IPR017855 SMAD-like_dom_sf
IPR001132 SMAD_dom_Dwarfin-type
IPR008984 SMAD_FHA_dom_sf
IPR036578 SMAD_MH1_sf
PANTHERiPTHR13703 PTHR13703, 1 hit
PfamiView protein in Pfam
PF03165 MH1, 1 hit
PF03166 MH2, 1 hit
SMARTiView protein in SMART
SM00523 DWA, 1 hit
SM00524 DWB, 1 hit
SUPFAMiSSF49879 SSF49879, 1 hit
SSF56366 SSF56366, 1 hit
PROSITEiView protein in PROSITE
PS51075 MH1, 1 hit
PS51076 MH2, 1 hit

Sequences (4+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 4 described isoforms and 8 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: P84022-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MSSILPFTPP IVKRLLGWKK GEQNGQEEKW CEKAVKSLVK KLKKTGQLDE
60 70 80 90 100
LEKAITTQNV NTKCITIPRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH
110 120 130 140 150
HELRAMELCE FAFNMKKDEV CVNPYHYQRV ETPVLPPVLV PRHTEIPAEF
160 170 180 190 200
PPLDDYSHSI PENTNFPAGI EPQSNIPETP PPGYLSEDGE TSDHQMNHSM
210 220 230 240 250
DAGSPNLSPN PMSPAHNNLD LQPVTYCEPA FWCSISYYEL NQRVGETFHA
260 270 280 290 300
SQPSMTVDGF TDPSNSERFC LGLLSNVNRN AAVELTRRHI GRGVRLYYIG
310 320 330 340 350
GEVFAECLSD SAIFVQSPNC NQRYGWHPAT VCKIPPGCNL KIFNNQEFAA
360 370 380 390 400
LLAQSVNQGF EAVYQLTRMC TIRMSFVKGW GAEYRRQTVT STPCWIELHL
410 420
NGPLQWLDKV LTQMGSPSIR CSSVS
Length:425
Mass (Da):48,081
Last modified:July 5, 2004 - v1
Checksum:i46DF5E8B371321AC
GO
Isoform 2 (identifier: P84022-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-68: MSSILPFTPP...NVNTKCITIP → MSCLHPRQTWKGAALVHRKAWWMG

Note: No experimental confirmation available.
Show »
Length:381
Mass (Da):43,237
Checksum:iD436B607B2677761
GO
Isoform 3 (identifier: P84022-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-105: Missing.

Show »
Length:320
Mass (Da):35,895
Checksum:iCB3D9B2D53AAC9E9
GO
Isoform 4 (identifier: P84022-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-195: Missing.

Note: No experimental confirmation available.
Show »
Length:230
Mass (Da):25,722
Checksum:iAFC64318B5EC08D1
GO

Computationally mapped potential isoform sequencesi

There are 8 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H3BVD1H3BVD1_HUMAN
Mothers against decapentaplegic hom...
SMAD3
213Annotation score:
H3BP09H3BP09_HUMAN
Mothers against decapentaplegic hom...
SMAD3
114Annotation score:
H0YKE2H0YKE2_HUMAN
Mothers against decapentaplegic hom...
SMAD3
112Annotation score:
H0YNV1H0YNV1_HUMAN
Mothers against decapentaplegic hom...
SMAD3
84Annotation score:
H0YL71H0YL71_HUMAN
Mothers against decapentaplegic hom...
SMAD3
92Annotation score:
H0YMP2H0YMP2_HUMAN
Mothers against decapentaplegic hom...
SMAD3
63Annotation score:
H3BQ00H3BQ00_HUMAN
Mothers against decapentaplegic hom...
SMAD3
156Annotation score:
H0YMY0H0YMY0_HUMAN
Mothers against decapentaplegic hom...
SMAD3
96Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti178E → EVGTWAAQAGL in BAA22032 (PubMed:9464505).Curated1
Sequence conflicti360F → L in BAH13315 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067051112A → V in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906854EnsemblClinVar.1
Natural variantiVAR_052021170I → V. Corresponds to variant dbSNP:rs35874463EnsemblClinVar.1
Natural variantiVAR_067047239E → K in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906853EnsemblClinVar.1
Natural variantiVAR_065578261T → I in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906851EnsemblClinVar.1
Natural variantiVAR_067048279R → K in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906852EnsemblClinVar.1
Natural variantiVAR_065579287R → W in LDS3. 1 PublicationCorresponds to variant dbSNP:rs387906850EnsemblClinVar.1
Natural variantiVAR_036474393P → L in a colorectal cancer sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0453481 – 195Missing in isoform 4. 1 PublicationAdd BLAST195
Alternative sequenceiVSP_0437931 – 105Missing in isoform 3. 1 PublicationAdd BLAST105
Alternative sequenceiVSP_0429001 – 68MSSIL…CITIP → MSCLHPRQTWKGAALVHRKA WWMG in isoform 2. 1 PublicationAdd BLAST68

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U68019 mRNA Translation: AAB80960.1
U76622 mRNA Translation: AAB18967.1
AB004930 Genomic DNA Translation: BAA22032.1
AF025300
, AF025293, AF025294, AF025295, AF025296, AF025297, AF025298, AF025299 Genomic DNA Translation: AAL68976.1
AK290881 mRNA Translation: BAF83570.1
AK298139 mRNA Translation: BAH12731.1
AK300614 mRNA Translation: BAH13315.1
AK316017 mRNA Translation: BAH14388.1
AC012568 Genomic DNA No translation available.
AC087482 Genomic DNA No translation available.
CH471082 Genomic DNA Translation: EAW77788.1
BC050743 mRNA Translation: AAH50743.1
CCDSiCCDS10222.1 [P84022-1]
CCDS45288.1 [P84022-2]
CCDS53950.1 [P84022-3]
CCDS53951.1 [P84022-4]
PIRiS71798
RefSeqiNP_001138574.1, NM_001145102.1 [P84022-3]
NP_001138575.1, NM_001145103.1 [P84022-2]
NP_001138576.1, NM_001145104.1 [P84022-4]
NP_005893.1, NM_005902.3 [P84022-1]
UniGeneiHs.727986
Hs.742270

Genome annotation databases

EnsembliENST00000327367; ENSP00000332973; ENSG00000166949 [P84022-1]
ENST00000439724; ENSP00000401133; ENSG00000166949 [P84022-2]
ENST00000537194; ENSP00000445348; ENSG00000166949 [P84022-4]
ENST00000540846; ENSP00000437757; ENSG00000166949 [P84022-3]
GeneIDi4088
KEGGihsa:4088
UCSCiuc002aqj.4 human [P84022-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U68019 mRNA Translation: AAB80960.1
U76622 mRNA Translation: AAB18967.1
AB004930 Genomic DNA Translation: BAA22032.1
AF025300
, AF025293, AF025294, AF025295, AF025296, AF025297, AF025298, AF025299 Genomic DNA Translation: AAL68976.1
AK290881 mRNA Translation: BAF83570.1
AK298139 mRNA Translation: BAH12731.1
AK300614 mRNA Translation: BAH13315.1
AK316017 mRNA Translation: BAH14388.1
AC012568 Genomic DNA No translation available.
AC087482 Genomic DNA No translation available.
CH471082 Genomic DNA Translation: EAW77788.1
BC050743 mRNA Translation: AAH50743.1
CCDSiCCDS10222.1 [P84022-1]
CCDS45288.1 [P84022-2]
CCDS53950.1 [P84022-3]
CCDS53951.1 [P84022-4]
PIRiS71798
RefSeqiNP_001138574.1, NM_001145102.1 [P84022-3]
NP_001138575.1, NM_001145103.1 [P84022-2]
NP_001138576.1, NM_001145104.1 [P84022-4]
NP_005893.1, NM_005902.3 [P84022-1]
UniGeneiHs.727986
Hs.742270

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1MHDX-ray2.80A/B1-132[»]
1MJSX-ray1.91A229-425[»]
1MK2X-ray2.74A220-425[»]
1OZJX-ray2.40A/B1-144[»]
1U7FX-ray2.60A/C228-425[»]
2LAJNMR-B202-211[»]
2LB2NMR-B178-189[»]
5OD6X-ray2.00A/B11-135[»]
5ODGX-ray2.12A/B11-135[»]
5XOCX-ray2.40A220-416[»]
ProteinModelPortaliP84022
SMRiP84022
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110263, 348 interactors
ComplexPortaliCPX-1 SMAD2-SMAD3-SMAD4 complex
CPX-12 SMAD3 homotrimer
CPX-3252 SMAD3-SMAD4 complex
CORUMiP84022
DIPiDIP-29720N
IntActiP84022, 188 interactors
MINTiP84022
STRINGi9606.ENSP00000332973

Chemistry databases

BindingDBiP84022
ChEMBLiCHEMBL1293258

Protein family/group databases

MoonDBiP84022 Predicted

PTM databases

iPTMnetiP84022
PhosphoSitePlusiP84022

Polymorphism and mutation databases

BioMutaiSMAD3
DMDMi51338669

Proteomic databases

EPDiP84022
MaxQBiP84022
PaxDbiP84022
PeptideAtlasiP84022
PRIDEiP84022
ProteomicsDBi57743
57744 [P84022-2]
57745 [P84022-3]

Protocols and materials databases

DNASUi4088
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000327367; ENSP00000332973; ENSG00000166949 [P84022-1]
ENST00000439724; ENSP00000401133; ENSG00000166949 [P84022-2]
ENST00000537194; ENSP00000445348; ENSG00000166949 [P84022-4]
ENST00000540846; ENSP00000437757; ENSG00000166949 [P84022-3]
GeneIDi4088
KEGGihsa:4088
UCSCiuc002aqj.4 human [P84022-1]

Organism-specific databases

CTDi4088
DisGeNETi4088
EuPathDBiHostDB:ENSG00000166949.15
GeneCardsiSMAD3
GeneReviewsiSMAD3
HGNCiHGNC:6769 SMAD3
HPAiCAB008094
CAB069409
HPA046386
HPA067203
MalaCardsiSMAD3
MIMi114500 phenotype
603109 gene
613795 phenotype
neXtProtiNX_P84022
OpenTargetsiENSG00000166949
Orphaneti284984 Aneurysm-osteoarthritis syndrome
91387 Familial thoracic aortic aneurysm and aortic dissection
PharmGKBiPA30526
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3701 Eukaryota
ENOG410XQKU LUCA
GeneTreeiENSGT00760000119091
HOGENOMiHOG000286018
HOVERGENiHBG053353
InParanoidiP84022
KOiK04500
OMAiSDHQMTH
OrthoDBiEOG091G082C
PhylomeDBiP84022
TreeFamiTF314923

Enzyme and pathway databases

ReactomeiR-HSA-1181150 Signaling by NODAL
R-HSA-1502540 Signaling by Activin
R-HSA-2173788 Downregulation of TGF-beta receptor signaling
R-HSA-2173789 TGF-beta receptor signaling activates SMADs
R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-3304356 SMAD2/3 Phosphorylation Motif Mutants in Cancer
R-HSA-3311021 SMAD4 MH2 Domain Mutants in Cancer
R-HSA-3315487 SMAD2/3 MH2 Domain Mutants in Cancer
R-HSA-3656532 TGFBR1 KD Mutants in Cancer
R-HSA-5689880 Ub-specific processing proteases
R-HSA-8941855 RUNX3 regulates CDKN1A transcription
R-HSA-8952158 RUNX3 regulates BCL2L11 (BIM) transcription
R-HSA-9008059 Interleukin-37 signaling
R-HSA-9013695 NOTCH4 Intracellular Domain Regulates Transcription
SignaLinkiP84022
SIGNORiP84022

Miscellaneous databases

ChiTaRSiSMAD3 human
EvolutionaryTraceiP84022
GeneWikiiMothers_against_decapentaplegic_homolog_3
GenomeRNAii4088
PROiPR:P84022
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000166949 Expressed in 229 organ(s), highest expression level in amniotic fluid
CleanExiHS_SMAD3
ExpressionAtlasiP84022 baseline and differential
GenevisibleiP84022 HS

Family and domain databases

Gene3Di2.60.200.10, 1 hit
3.90.520.10, 1 hit
InterProiView protein in InterPro
IPR013790 Dwarfin
IPR003619 MAD_homology1_Dwarfin-type
IPR013019 MAD_homology_MH1
IPR017855 SMAD-like_dom_sf
IPR001132 SMAD_dom_Dwarfin-type
IPR008984 SMAD_FHA_dom_sf
IPR036578 SMAD_MH1_sf
PANTHERiPTHR13703 PTHR13703, 1 hit
PfamiView protein in Pfam
PF03165 MH1, 1 hit
PF03166 MH2, 1 hit
SMARTiView protein in SMART
SM00523 DWA, 1 hit
SM00524 DWB, 1 hit
SUPFAMiSSF49879 SSF49879, 1 hit
SSF56366 SSF56366, 1 hit
PROSITEiView protein in PROSITE
PS51075 MH1, 1 hit
PS51076 MH2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSMAD3_HUMAN
AccessioniPrimary (citable) accession number: P84022
Secondary accession number(s): A8K4B6
, B7Z4Z5, B7Z6M9, B7Z9Q2, F5H383, O09064, O09144, O14510, O35273, Q92940, Q93002, Q9GKR4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 5, 2004
Last sequence update: July 5, 2004
Last modified: November 7, 2018
This is version 176 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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